N-Boc-(S)-Ala-(R)-boroPro (1S,2S,3R,5S)-pinanediol ester | 162185-13-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-Boc-(S)-Ala-(R)-boroPro (1S,2S,3R,5S)-pinanediol ester
• 英文别名: tert-butyl N-[(2S)-1-oxo-1-[(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]pyrrolidin-1-yl]propan-2-yl]carbamate
• CAS: 162185-13-9
• 化学式: C₂₂H₃₇BN₂O₅
• 分子量: 420.357
• InChiKey: UDRXZJDRLDLQQU-FHAIXYJRSA-N

物化性质

• 沸点：
  529.3±45.0 °C(Predicted)
• 密度：
  1.14±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.16
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.91
• 拓扑面积：
  77.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-Boc-(S)-Ala-(R)-boroPro (1S,2S,3R,5S)-pinanediol ester 在 三氯化硼 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 生成 Ala-boro-Pro
  参考文献：
  名称：

  Pro-Soft Val-boroPro: A Strategy for Enhancing in Vivo Performance of Boronic Acid Inhibitors of Serine Proteases

  摘要：

  Val-boroPro, 1, is a potent, but relatively nonspecific inhibitor of the prolyl peptidases. It has antihyperglycemic activity from inhibition of DPPIV but also striking anticancer activity and a toxicity for which the mechanisms are unknown. 1 cyclizes at physiological pH, which attenuates its inhibitory potency > 100-fold, which is a "soft drug" effect. Here we show that this phenomenon can be exploited to create prodrugs with unique properties and potential for selective in vivo targeting. Enzyme-mediated release delivers 1 to the target in the active form at physiological pH; cyclization attenuates systemic pharmacological effects from subsequent diffusion. This "pro-soft" design is demonstrated with a construct activated by and targeted to DPPIV, including in vivo results showing improved antihyperglycemic activity and reduced toxicity relative to I. Pro-soft derivatives of 1 can help to illuminate the mechanisms underlying the three biological activities, or to help localize 1 at a tumor and thereby lead to improved anticancer agents with reduced toxicity. The design concept can also be applied to a variety of other boronic acid inhibitors.

  DOI：

  10.1021/jm100972f
• 作为产物：
  描述：

  L-boroPro-pn 、 N-叔丁氧羰基-L-丙氨酸 在 盐酸 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 N-Boc-(S)-Ala-(R)-boroPro (1S,2S,3R,5S)-pinanediol ester
  参考文献：
  名称：

  [EN] SOFT PROTEASE INHIBITORS AND PRO-SOFT FORMS THEREOF
  [FR] INHIBITEURS LEGERS DE PROTEASES ET LEURS PRO-FORMES LEGERES

  摘要：

  公开号：

  WO2007100374A3

文献信息

• [EN] SOFT PROTEASE INHIBITORS AND PRO-SOFT FORMS THEREOF<br/>[FR] INHIBITEURS LEGERS DE PROTEASES ET LEURS PRO-FORMES LEGERES
  申请人：TUFTS COLLEGE

  公开号：WO2007100374A3

  公开（公告）日：2008-11-13
• Pro-Soft Val-boroPro: A Strategy for Enhancing in Vivo Performance of Boronic Acid Inhibitors of Serine Proteases
  作者：Sarah E. Poplawski、Jack H. Lai、David G. Sanford、James L. Sudmeier, Wengen Wu、William W. Bachovchin

  DOI：10.1021/jm100972f

  日期：2011.4.14

  Val-boroPro, 1, is a potent, but relatively nonspecific inhibitor of the prolyl peptidases. It has antihyperglycemic activity from inhibition of DPPIV but also striking anticancer activity and a toxicity for which the mechanisms are unknown. 1 cyclizes at physiological pH, which attenuates its inhibitory potency > 100-fold, which is a "soft drug" effect. Here we show that this phenomenon can be exploited to create prodrugs with unique properties and potential for selective in vivo targeting. Enzyme-mediated release delivers 1 to the target in the active form at physiological pH; cyclization attenuates systemic pharmacological effects from subsequent diffusion. This "pro-soft" design is demonstrated with a construct activated by and targeted to DPPIV, including in vivo results showing improved antihyperglycemic activity and reduced toxicity relative to I. Pro-soft derivatives of 1 can help to illuminate the mechanisms underlying the three biological activities, or to help localize 1 at a tumor and thereby lead to improved anticancer agents with reduced toxicity. The design concept can also be applied to a variety of other boronic acid inhibitors.